rs7190823

Variant names:

• chr16-89799635-T-C
• rs7190823
• NM_000135.4:c.796A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.796A>G​(p.Thr266Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 1,607,974 control chromosomes in the GnomAD database, including 184,200 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T266M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.53 (23670 hom., cov: 33)
  • Exomes 𝑓: 0.45 (160530 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 0.671
• Publications: 86 publications found

Genes affected

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1698945E-6).
• BP6: Variant 16-89799635-T-C is Benign according to our data. Variant chr16-89799635-T-C is described in ClinVar as Benign. ClinVar VariationId is 134294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000135.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.796A>G	p.Thr266Ala	missense	Exon 9 of 43	NP_000126.2
	FANCA	NM_001286167.3		c.796A>G	p.Thr266Ala	missense	Exon 9 of 43	NP_001273096.1
	FANCA	NM_001018112.3		c.796A>G	p.Thr266Ala	missense	Exon 9 of 11	NP_001018122.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.796A>G	p.Thr266Ala	missense	Exon 9 of 43	ENSP00000373952.3
	FANCA	ENST00000563673.5	TSL:1	c.796A>G	p.Thr266Ala	missense	Exon 9 of 10	ENSP00000456443.1
	FANCA	ENST00000534992.5	TSL:1	c.796A>G	p.Thr266Ala	missense	Exon 9 of 11	ENSP00000443675.1

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80719 AN: 152034 Hom.: 23636 Cov.: 33

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.465

GnomAD2 exomes AF: 0.521 AC: 130900 AN: 251338 AF XY: 0.509

Gnomad AFR exome AF: 0.725

Gnomad AMR exome AF: 0.668

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.984

Gnomad FIN exome AF: 0.469

Gnomad NFE exome AF: 0.385

Gnomad OTH exome AF: 0.454

GnomAD4 exome AF: 0.453 AC: 658793 AN: 1455822 Hom.: 160530 Cov.: 33 AF XY: 0.454 AC XY: 328778 AN XY: 724642

African (AFR) AF: 0.723 AC: 24115 AN: 33344

American (AMR) AF: 0.653 AC: 29193 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8421 AN: 26098

East Asian (EAS) AF: 0.980 AC: 38877 AN: 39670

South Asian (SAS) AF: 0.589 AC: 50746 AN: 86148

European-Finnish (FIN) AF: 0.461 AC: 24611 AN: 53354

Middle Eastern (MID) AF: 0.333 AC: 1921 AN: 5762

European-Non Finnish (NFE) AF: 0.409 AC: 452720 AN: 1106550

Other (OTH) AF: 0.468 AC: 28189 AN: 60192

GnomAD4 genome AF: 0.531 AC: 80814 AN: 152152 Hom.: 23670 Cov.: 33 AF XY: 0.540 AC XY: 40187 AN XY: 74378

African (AFR) AF: 0.717 AC: 29755 AN: 41508

American (AMR) AF: 0.545 AC: 8320 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1135 AN: 3468

East Asian (EAS) AF: 0.981 AC: 5095 AN: 5192

South Asian (SAS) AF: 0.628 AC: 3028 AN: 4818

European-Finnish (FIN) AF: 0.474 AC: 5008 AN: 10576

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27132 AN: 67994

Other (OTH) AF: 0.471 AC: 994 AN: 2110

Alfa AF: 0.444 Hom.: 60668

Bravo AF: 0.547

TwinsUK AF: 0.436 AC: 1616

ALSPAC AF: 0.409 AC: 1576

ESP6500AA AF: 0.726 AC: 3190

ESP6500EA AF: 0.394 AC: 3386

ExAC AF: 0.516 AC: 62710

Asia WGS AF: 0.788 AC: 2740 AN: 3478

EpiCase AF: 0.384

EpiControl AF: 0.372

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Fanconi anemia complementation group A (7)
-	-	2	not provided (2)
-	-	2	not specified (3)
-	-	1	Fanconi anemia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.2
DANN	Benign	0.16
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.023	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.1	N
PhyloP100		0.67
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.084
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.086
ClinPred		0.0032	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.078
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7190823; hg19: chr16-89866043; COSMIC: COSV107492121; COSMIC: COSV107492121;